1. Field of the Invention
The invention generally concerns protein mediated neurological disorders. In particular, the invention provides new methods to delay the onset and/or progression of tauopathies.
2. Description of Related Art
A wide variety of neurodegenerative disorders involve accumulation of insoluble tau protein. These disorders are collectively known as tauopathies due to the presence of tau tangles though, their clinical manifestation vary widely. One well-known tauopathy, Alzheimer's disease (AD) is defined neuropathologically by the accumulation of beta-amyloid plaques and neurofibrillary tangles (NFT) containing tau protein. NFTs in AD have been found to consist of hyperphosphorylated forms of the tau protein. Hyperphosphorylated tau exhibits reduced ability to bind and stabilize microtubules and can self-aggregate to form insoluble paired helical filaments (PHFs), which comprise NFTs (Gustke et al., 1992; Bramblett et al., 1993; Alonso et al., 1996). The incidence of NFTs is positively correlated with cognitive deficit and neuronal loss in AD (Arriagada et al., 1992; Gomez-Isla et al., 1997), and the discovery that mutations in the tau gene underlie autosomal dominant forms of frontotemporal dementia suggests that pathological changes in tau can serve as a principal cause of neurodegeneration and cognitive impairment (Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998). In view of this, tau phosphorylation has been studies as a possible mediator of tauopathies.
Exposure to a range of environmental insults, or stresses, can activate tau kinases and induce tau phosphorylation (tau-P) in the rodent central nervous system (CNS) (e.g., Korneyev et al., 1995; Papasozomenos, 1996; Korneyev, 1998; Yanagisawa et al., 1999; Planel et al., 2001, 2004; Arendt et al., 2003; Feng et al., 2005). This effect has been reported consistently in the hippocampal formation, a key structure in learning and memory, and the initial site of tau pathology in AD (Braak and Braak, 1991). Although acute stress-induced tau-P is reversible, the mechanisms that govern this phenomenon are unknown, and it is not clear whether and how it may be manifest under chronic stress conditions. Addressing these questions may better define the elusive links between the stress axis and AD-related pathogenic processes, as increased exposure and/or sensitivity to stress in humans and rodent models confers increased risk of dementia and AD neuropathology (Wilson et al., 2003; Jeong et al., 2006).
Warranting consideration in this respect are glucocorticoids, dominant stress hormones whose elevated levels in aging have been linked to increased neuronal vulnerability in hippocampus (Sapolsky et al., 1985, 1986). However, acute stress-induced tau-P is reportedly unaffected in adrenalectomized mice (Korneyev et al., 1995), suggesting that glucocorticoid secretion may not be pivotally involved. Alternatively, the corticotropin-releasing factor (CRF) signaling system plays an essential role in initiating pituitary-adrenal responses to stress, and has been implicated as a transmitter/modulator in CNS systems that mediate complementary autonomic and behavioral adjustments, earning consideration as a general mediator/integrator of stress adaptations (Chadwick et al., 1993). CRF and related ligands (urocortins 1-3) exert their biological effects via two G-protein coupled receptors (CRF-R1, CRF-R2) that are differentially distributed in brain (Van Pett et al., 2000), and exert convergent effects on a range of stress-related endpoints (Bale and Vale, 2004). CRF-R ligands can confer neuroprotection, in vitro, by altering amyloid precursor protein (APP) processing and suppressing tau kinases, and reduced central CRF expression has been documented early in AD progression (Rehman, 2002; Bayatti and Behl, 2005). Furthermore, studies examining the effects of CRF-R signaling on apoptotic cell death in neurons indicated that CRF-R2 agonists had no effect on neuronal death while CRF-R1 agonist has a protective effect (Pedersen et al., 2002). These results lead many in the field to contemplate that CRF-R1 agonist might have use as therapeutics in AD (Pedersen et al., 2002; U.S. Publn. 20030186867). However, to date the precise role of CRF-R signaling in the development and progression of tauopathies has remained unclear.